Abstract: Dementia due to Alzheimer's Disease (AD) disproportionately impacts racial and ethnic minorities and the socioeconomically disadvantaged?populations often exposed to neighborhood disadvantage, a condition associated with education, health behaviors, mortality and disease. Although studies have linked neighborhood to diseases such as diabetes and cancer, very little is known about the effect of neighborhood disadvantage on development of dementia. A better understanding of the interactions among social and biological processes is necessary to design effective interventions to ameliorate AD disparities. We have created and validated neighborhood-level quantifications of socioeconomic contextual disadvantage for the full US?over 34 million Zip+4 codes?employing the latest American Community Survey data. This metric--the Area Deprivation Index (ADI)--incorporates poverty, education, housing and employment indicators; predicts disparity-related health outcomes; and can be used to establish a `dose' and timing of exposure to lifetime neighborhood disadvantage. Our long-term objective is to examine the impact, mediators and moderators of exposure to socioeconomic contextual disadvantage on the development of AD-specific pathologic features, vascular burden and cognitive decline. Our short-term objective is to establish the necessary preliminary assessments, infrastructure and methods to enable us to further our long-term goal. In addition to capitalizing on the data available through the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (ADRC), we will create detailed residential histories for each subject (N~1918). Furthermore, since post-mortem brain tissue allows for characterization of AD neuropathological burden, we will work with the US Census to validate a novel technique for the creation of lifetime residential histories for specimens housed within two ADRC?based brain banks (N~2745). Aim 1: Determine the impact of the cumulative dose and timing of neighborhood disadvantage exposure, by ADI, on cognitive function and cognitive change over time; and Aim 2: on AD-specific markers indexed by neuroimaging (amyloid and tau PET) and CSF (P-tau, A?42). Secondary outcomes include volumetric MRI and markers of neurovascular health. Exploratory Aims 1a, 2a: Using existing data, define the extent to which race/ethnicity, age, gender and APOE4 status modify, and income, education, comorbidity and health-behaviors mediate, these relationships. Aim 3: Validate a novel technique for the creation of lifetime residential histories for brains within two ADRC based brain banks (Wisconsin and University of California-San Diego) in partnership with the US Census. Exploratory Aim 3a: Using existing brain bank data, define the extent to which the cumulative dose and timing of neighborhood disadvantage exposure, by ADI, impacts neuropathologic diagnosis, features. Impact: The project will better understanding of the fundamental mechanistic linkages between neighborhood disadvantage and AD, providing a potential pathway to new therapeutics and directly responsive to NIA mission.